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Corso di Laurea Magistrale in Farmacia

Universita’ degli Studi di Milano

Tecnologia e Legislazione Farmaceutiche I - 9 CFU

Prof. Andrea Gazzaniga

Rilascio Modificato Orale – Ritardato/Pulsatile – Parte II

film di EC e HPMC (75:25)

nucleo (unità singole) contenente il farmaco ed un agente idrofilo rigonfiante (polivinilalcol)

Swelling Controlled Release System (SCRS)

Morita R. et al., J. Control. Rel. 63, 297 (2000)

&

film semipermeabile di cellulosa acetato

nucleo (pellets) contenente il farmaco (paracetamolo) e un agente osmoattivo (NaCl)

Schultz P. and Kleinebudde P., J. Control. Rel. 47, 181 (1997)

&

film di etilcellulosa (insolubile, permeabile)

nucleo (compresse o pellets) contenente il farmaco, agenti idrofili rigonfianti (Na carbossimetilcellulosa) e osmoattivi (NaCl, sorbitolo)

Amidon G.L. and Leesman G.D., US Patent 5 229 131 (1993)

&

film di etilcellulosa

nucleo (compresse) contenente il farmaco eduna miscela di acido citrico e sodiobicarbonato

Kroegel I. and Bodmeier R., Int. J. Pharm. 187, 175 (1999)

- sistemi réservoir

(delayed/pulsatile release)

Sistemi orali a rilascio ritardato/pulsante

- nucleo contenente il principio attivo

- rivestimento ritardante il rilascio

• lacerazione per aumento della pressione interna

•dissoluzione e/o erosione

• aumento della permeabilità


Narisawa S. et al., Pharm. Res. 11(1), 111 (1994)

Sigmoidal Release System (SRS)

- sistemi réservoir

(delayed/pulsatile release)

Sistemi orali a rilascio ritardato/pulsante

- nucleo contenente il principio attivo

- rivestimento ritardante il rilascio

• lacerazione per aumento della pressione interna

•dissoluzione e/o erosione


Wax mixturespray-coating in rotating pan or fluid bedat 80-90°C

Core (tablet)

Pozzi F. et al., J. Control. Rel., 31, 99 (1994)

Time-Clock® System

Stage 1 - Erosion of the wax layer [surfactants/hydrophilic agents]Stage 2 - Rapid release of the active

Salbutamol plasma profiles following oral administration of conventional

dosage form and TIME CLOCK

adapted from Pozzi F. et al., J. Control. Rel., 31, 99 (1994)

Time-Clock® System

0

5

10

15

20

0 120 240 360 480 600

Time (min)

Pla

sm

a c

on

cen

trati

on

(n

g/m

l)

conventional dosage form

Time-Clock

Chronotopic™ System

Eur. J. Pharm. Biopharm., 40 (4) 246-250 (1994)

Oral ChronotopicTM Drug Delivery Systems:Achievement of Time and / or Site Specificity

Andrea Gazzaniga*,Maria Edvige Sangalli**,Ferdinando Giordano**

- * University of Milan, Institute for Pharmaceutical Chemistry, Milan, Italy

- ** University of Pavia, Department of Pharmaceutical Chemistry, Pavia, Italy

Hydrophilic swellable polymeric layer(HPMC, different viscosity grades)


Gazzaniga A. et al., Eur. J. Pharm. Biopharm. 40(4), 246 (1994)

Stage 0 - Dissolution of gastric resistant filmStage 1 - Swelling/Erosion of polymeric layerStage 2 - Rapid release of the active

Drug-containing core [single/multiple unit]

glassy rubberydrug particles

amou

ntre

leas

ed

time


The slow interaction polymer/fluid lead to the formation

of a gel [glassy/rubbery]


amou

ntre

leas

ed

time

••

•••• •••• •••• •••• •••••

• •••••

no release


Rapid or slow release depending on core

characteristics


amou

ntre

leas

ed

time

••

•••• •••• •••• •••• •••••

• •••••

Lag phase physical-chemical characteristicsand coating level of the retarding polymer

no releaselag phase

press-coating

spray-coating

- large-scale production implies use of special presses

- difficult core centering with consequences on coating thickness uniformity


How to prepare the retarding layer?

- technical obstacles to acceptable sprayability and reasonable

processing time [hydroalcoholic dispersions/viscosity]

- polymers [high viscosity HPMC] never used before as coating agents.

Chronotopic™ Systempress-coating Methocel ® K100 LV


limitations in the design flexibility owing to the large amount of coating needed

press-coating Methocel ® K100 LV

0

40

80

% released

0 120 240 360 480 600

time (min)

Release profile of Verapamil.HCl from Methocel® K100 LV press-coated systems with150% weight gain – 177.6 mg/cm2 coating polymer amount [tablet cores 60 mg]


limitations in the design flexibility owing to the large amount of coating needed

press-coating Methocel ® K100 LV

Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994)

quite difficult to avoid the relatively and undesired long

diffusion phase

Chronotopic™ Systemspray-coating hydroalcoholic dispersions Methocel ®K15M

Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w)

Large scale production limitations due to the use of organic solvents


0 100 200 300 400

0

20

40

60

80

100

tablet core

7,6 mg/cm 2

15,2 mg/cm 2

22,8 mg/cm 2

30,4 mg/cm 2

time (min)

% r

elea

sed

Release profiles of indomethacin from uncoated cores (4 mm diameter, 20 mg model drug) andsystems spray-coated [rotating pan] with increasing amounts, mg/cm2, of high viscosity HPMC -[hydro-alcoholic dispersion of Methocel K15M - 5% w/w]




Relationship between applied polymer amount and lag time for high viscosity HPMC spray-coatedunits [rotating pan, hydro-alcoholic dispersion of Methocel K15M- 5% w/w]

0 10 20 30 400

100

200

300 Lag time (min)

Applied polymer amount (mg/cm 2)






systematic study to select the most convenient HPMC aqueous coating systems

Comparative evaluation of different HPMC viscosity grades, Methocel® E5, E50 and K4M, in terms of process feasibility and performances as coating agents in

aqueous solution

unsolved issuehow to switch to aqueous solvents ?

Spray–coating with aqueous solutions of different HPMC viscosity grade

SEM photomicrographs of cross-sectioned systems coated withMethocel®E5 (top), E50 (middle) and K4M (bottom) aqueoussolutions at 16, 8 and 2% w/v, respectively (magnification 47x)



M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)

Release profiles obtained from uncoated cores and systems coated (w.g. 20%) withMethocel® E5, E50 and K4M aqueous solutions at 16, 8 and 2% w/v, respectively




0

25

50

75

100

0 30 60 90 120 150

time (min)

dru

g re

leas

ed (

%)

uncoated

Methocel ® E5

Methocel ® E50

Methocel ® K4M

-process time necessary for spray-coating

-ability to delay drug release

-final dimensions of the coated units

-possibility of finely tuning the lag phase duration



… Methocel E50 … was selected for further studies since it

affords the best balanceamong:

finally

corew.g. 22%w.g. 35%w.g. 50%w.g. 58%w.g. 73%w.g. 92%w.g. 115%w.g. 142%

27024021018015012090603000

20

40

60

80

100

time (min)

% released

Release profiles of a tracer substance from uncoated cores (6.7 mm diameter, 180

mg weight, 2.3% methyl-4-hydroxybenzoate ) and cores coated with increasing amountof low viscosity HPMC (Methocel® E50)

Spray–coating with aqueous solutions of Methocel ® E 50


A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995)

fine tuning of lag time

14012010080604020000

30

60

90

120

150

180

210

weight gain (%)

Lag time (min)

Relationship between weight gain and lag time for low viscosity HPMC(Methocel® E50)-coated units (fluid bed).




Relationship between weight gain and layer thickness for Methocel® E50 caoted-units.

0.0

0.4

0.8

1.2

thickness (mm)

0 50 100 150

weight gain (%)




Release profiles of acetaminophenobtained from Methocel® E50-coatedsystems at different pH (weight gain:

20% - coating thickness 277 µm).

pH=1.5

0

20

40

60

80

100

0 20 40 60 80

100 % released

pH=11.5

0

20

40

60

80

0 15 30 45 60 75 90

time (min)time (min)

pH=7.5

0

20

40

60

80

100

0 20 40 60 80

% released

% released

time (min)




t10% as a function of the medium ionic strength for Methocel®E50-coated systems (weightgain 20%, coating thickness 277 µm) - bars represent s.d.




0

40

80

120

0 0.1 0.2 0.3 0.4

ionic strength

ionic strength-independent lag phase

t10 % (min)Lag time

in the physiological range 0.01-0.166

top spray fluid bed equipment

tangential spray-coating

rotor insertpowder layering

spray-coating


… there was still room for improvement in process time…

progressive decrease in process time

Tablets coated by spray-coating, top-spray fluid bed (thickness 475 µm, amount 49 mg/cm2)

Tablets coated by powder layering, rotary tangential fluid bed (thickness 1020 µm, amount 48 mg/cm2)

Tablets coated by spray-coating, rotary tangential fluid bed (thickness 375 µm, amount 48 mg/cm2)

0

20

40

60

0 10 20 30 40 50 60

<2 hours13 hours

6 hours

Lag time (min)


Weight gain (%)

layer thickness ~ 450 µm, ~ 50 mg/cm2)

progressive decrease in process time


… pellets large units … design flexibility


Model drug: Antipyrine (50 mg)

Disintegrating core: 6 mm, 158 mg

Retarding layer: Methocel®E50 (thickness 325, 575 and 1020 µm)

Spraying equipment: Fluid bed (Uniglatt, Glatt GmbH)

Volunteers: 4 healthy male (age 36-45, weight 70-80Kg)

Sampling Antipyrine was quantified in saliva by HPLC

in vivo study on Antipyrine-containing units


saliva and blood concentrations of Antipyrine are known to be consistent

0

20

40

60

80

100

0 2 4 6 8 10 12 14

F

F25

F50

F100

time (h)

drug released (%)

In vitro release profiles of antipyrine from uncoated cores (formulation F) and unitscoated with different amounts of HPMC (formulations F25, F50 and F100, coatingthickness 325, 575 and 1020 µm); paddle, SIF, 370.5°C, 100 rpm, mean of 6 replicates.

HPMC coated units

Chronotopic™ SystemAdapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)

0.0

0.3

0.6

0.9

1.2

1.5

1.8

0 2 4 6

time (h)

saliva concentration (µg/ml)

F

F25

F50

F100

0.0

0.3

0.6

0.9

1.2

1.5

1.8

0 8 16 24 32 40 48time (h)

saliva concentration (µg/ml)

Average antipyrine saliva levels after oral administration of uncoated cores(formulation F) and units coated with differing amounts of HPMC (formulationsF25, F50 and F100, coating thickness 325, 575 and 1020 µm).

HPMC coated units


Relationship between in vivo t10% (time to 10% Cmax) and coating thickness for formulations F25, F50 and

F100 [coating thickness 325, 575 and 1020 µm]

HPMC coated units


y = 0,2812x - 58,195

R 2 = 0,9993

0

60

120

180

240

300

360

0 200 400 600 800 1000 1200

coating thickness (µm)

in vivo lag time T10% (min)

Relationship between in vivo and in vitro lag time for systems coated withMethocel®E50 up to 325, 575 and 1020 µm layer thickness.

HPMC coated units


0

2

4

0 2 4

in vivo lag time T10% (hours)

in vitro lag time T10% (hours)

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